Hypoglycemia is the most prevalent clinical complication in the daily management of insulin-treated people with diabetes and hypoglycemia continues to be the limiting factor in the glycemic management of diabetes. For insulin treated people with diabetes, concern regarding the hazardous potential for severe hypoglycemia to cause brain damage continues to be a very real barrier in striving to fully realize the benefits associated with intensive glycemic control. Experiments in animals demonstrate that severe hypoglycemia reproducibly leads to brain damage and cognitive impairments. In patients with diabetes however, the clinical consequences of severe hypoglycemia remains an area of intense controversy because there is a marked variability in reports documenting extent of cognitive damage. Preliminary studies presented below demonstrate the novel finding that glycemic control can significantly either improve or worsen the extent of brain damage following an episode of severe hypoglycemia. The overall hypothesis in this proposal is that the metabolic derangements associated with diabetes worsen the extent of neuronal damage following an episode of severe insulin-induced hypoglycemia and that both intensive glycemic control and specific neuroprotective agents can effectively mitigate against this type of brain damage and its associated cognitive deficits. This proposal seeks to develop approaches to prevent the detrimental effects of hypoglycemia on the brain. The specific aims to be addressed in this research proposal are to; 1) determine whether diabetes augments the extent of brain damage and cognitive decline following an episode of severe hypoglycemia and explore the possibility that insulin acts as a neuroprotective agent to mitigate against increased brain damage and cognitive deficits, 2) explore the possibility that recurrent antecedent hypoglycemia acts to pre-condition the brain thus protecting against the brain damaging effects of severe hypoglycemia in control and diabetic rats, and to identify the likely mediators of this protective phenomena, and 3) determine the efficacy of pharmaceutical agents in preventing brain damage and cognitive dysfunction following an episode of severe hypoglycemia.